Highly active retroviral therapy (HAART) in HIV infected patients has had a profound effect on the progression of AIDS, decreases plasma viral load and can result in improvements in immune function. However, the effects of HAART on the CNS are more variable and the reduction in viral load in the cerebrospinal fluid does not necessarily mirror reductions in the plasma (refs). In addition, resting CD4+ lymphocytes in the peripheral blood constitute a stable, long-lived reservoir of latently infected cells. Monocytes in the blood of HW-infected individuals on HAART also express virus, thus additional viral reserviors exist. The CNS is likely to harbor latently and persistently infected cells, since antiretroviral drugs either do not penetrate the blood brain barrier or do not reach equivalent levels in the brain. In this project SIV-infected macaques treated with combination antiretroviral therapy (CART) will be used to identify CNS reservoirs in vivo and to identify the mechanisms that establish and maintain HIV/SIV latency and/or persistence and contribute to the development of CNS disease. The hypothesis for this project is that latent and persistent reserviors of HIV/SW are established early in the CNS and that viral latency or persistence is maintained in macrophages/microglia and astrocytes in the CNS in infected individuals lifelong. Further, within specific CNS cells mechanisms exist that regulate virus gene expression and these mechanisms will be examined in SIV macaques infected and treated with CART. The aims of this project are to examine when a stable reservoir of SIV is established in the brain; whether control of virus replication in the peripheral blood by CART is accompanied by lower levels of viral replication in the brain; to identify the effect of CART on the level of regulation of SIV gene expression in brain from acute through asymptomatic and late stage infection andto examine mechanisms that control early virus replication in the CNS in SW infected macaques treated/untreated with CART in the brain and CSF in SIV infected macaques.